Method and apparatus for application of a neural stimulus

ABSTRACT

A method of applying a neural stimulus with an implanted electrode array involves applying a sequence of stimuli configured to yield a therapeutic effect while suppressing psychophysical side effects. The stimuli sequence is configured such that a first stimulus recruits a portion of the fibre population, and a second stimulus is delivered within the refractory period following the first stimulus and the second stimulus being configured to recruit a further portion of the fibre population. Using an electrode array and suitable relative timing of the stimuli, ascending or descending volleys of evoked responses can be selectively synchronised or desynchronised to give directional control over responses evoked.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/514,650, filed on Oct. 29, 2021, which is a continuation of U.S.patent application Ser. No. 17/501,823, filed on Oct. 14, 2021, which isa continuation of U.S. patent application Ser. No. 17/489,710, filed onSep. 29, 2021, which is a continuation of U.S. patent application Ser.No. 17/478,793, filed on Sep. 17, 2021, which is a continuation of U.S.patent application Ser. No. 17/031,749, filed on Sep. 24, 2020, which isa continuation of U.S. patent application Ser. No. 15/846,069, filed onDec. 18, 2017, which is a continuation of U.S. patent application Ser.No. 14/844,929, filed on Sep. 3, 2015 and issued as U.S. Pat. No.9,872,990, which is a continuation of U.S. patent application Ser. No.14/117,586, filed on May 13, 2014 and issued as U.S. Pat. No. 9,155,892on Oct. 13, 2015, which is a U.S. National Stage Application under 35U.S.C. § 371 of International Application No. PCT/AU2012/000515, filedon May 11, 2012, which claims priority to Australian Provisional PatentApplication No. AU2011901828 filed May 13, 2011 and AustralianProvisional Patent Application No. AU2011901829 filed May 13, 2011, allof which are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to application of a neural stimulus, andin particular relates to applying a neural stimulus in a controlledmanner by using one or more electrodes implanted proximal to the neuralpathway. The present invention also relates to controlling a neuralresponse to a stimulus, and in particular relates to measurement of acompound action potential by using one or more electrodes implantedproximal to the neural pathway, in order to provide feedback to controlsubsequently applied stimuli.

BACKGROUND OF THE INVENTION

There are a range of situations in which it is desirable to apply neuralstimuli in order to give rise to a compound action potential (CAP). Forexample, neuromodulation is used to treat a variety of disordersincluding chronic pain, Parkinson's disease, and migraine. Aneuromodulation system applies an electrical pulse to tissue in order togenerate a therapeutic effect. When used to relieve chronic pain, theelectrical pulse is applied to the dorsal column (DC) of the spinalcord. Such a system typically comprises an implanted electrical pulsegenerator, and a power source such as a battery that may be rechargeableby transcutaneous inductive transfer. An electrode array is connected tothe pulse generator, and is positioned in the dorsal epidural spaceabove the dorsal column. An electrical pulse applied to the dorsalcolumn by an electrode causes the depolarisation of neurons, andgeneration of propagating action potentials. The fibres being stimulatedin this way inhibit the transmission of pain from that segment in thespinal cord to the brain. To sustain the pain relief effects, stimuliare applied substantially continuously, for example at 100 Hz.

While the clinical effect of spinal cord stimulation (SCS) is wellestablished, the precise mechanisms involved are poorly understood. TheDC is the target of the electrical stimulation, as it contains theafferent Aβ fibres of interest. Aβ fibres mediate sensations of touch,vibration and pressure from the skin, and are thickly myelinatedmechanoreceptors that respond to non-noxious stimuli. The prevailingview is that SCS stimulates only a small number of Aβ fibres in the DC.The pain relief mechanisms of SCS are thought to include evokedantidromic activity of Aβ fibres having an inhibitory effect, and evokedorthodromic activity of Aβ fibres playing a role in pain suppression. Itis also thought that SCS recruits Aβ nerve fibres primarily in the DC,with antidromic propagation of the evoked response from the DC into thedorsal horn thought to synapse to wide dynamic range neurons in aninhibitory manner.

Neuromodulation may also be used to stimulate efferent fibres, forexample to induce motor functions. In general, the electrical stimulusgenerated in a neuromodulation system triggers a neural action potentialwhich then has either an inhibitory or excitatory effect. Inhibitoryeffects can be used to modulate an undesired process such as thetransmission of pain, or to cause a desired effect such as thecontraction of a muscle.

The action potentials generated among a large number of fibres sum toform a compound action potential (CAP). The CAP is the sum of responsesfrom a large number of single fibre action potentials. The CAP recordedis the result of a large number of different fibres depolarising. Thepropagation velocity is determined largely by the fibre diameter and forlarge myelinated fibres as found in the dorsal root entry zone (DREZ)and nearby dorsal column the velocity can be over 60 ms⁻¹. The CAPgenerated from the firing of a group of similar fibres is measured as apositive peak potential P1, then a negative peak N1, followed by asecond positive peak P2. This is caused by the region of activationpassing the recording electrode as the action potentials propagate alongthe individual fibres. An observed CAP signal will typically have amaximum amplitude in the range of microvolts, whereas a stimulus appliedto evoke the CAP is typically several volts.

For effective and comfortable operation, it is necessary to maintainstimuli amplitude or delivered charge above a recruitment threshold,below which a stimulus will fail to recruit any neural response. It isalso necessary to apply stimuli which are below a comfort threshold,above which uncomfortable or painful percepts arise due to increasingrecruitment of Aδ fibres which are thinly myelinated sensory nervefibres associated with acute pain, cold and pressure sensation. Inalmost all neuromodulation applications, a single class of fibreresponse is desired, but the stimulus waveforms employed can recruitother classes of fibres which cause unwanted side effects, such asmuscle contraction if motor fibres are recruited. The task ofmaintaining appropriate neural recruitment is made more difficult byelectrode migration and/or postural changes of the implant recipient,either of which can significantly alter the neural recruitment arisingfrom a given stimulus, depending on whether the stimulus is appliedbefore or after the change in electrode position or user posture.Postural changes alone can cause a comfortable and effective stimulusregime to become either ineffectual or painful.

Any discussion of documents, acts, materials, devices, articles or thelike which has been included in the present specification is solely forthe purpose of providing a context for the present invention. It is notto be taken as an admission that any or all of these matters form partof the prior art base or were common general knowledge in the fieldrelevant to the present invention as it existed before the priority dateof each claim of this application.

Throughout this specification the word “comprise”, or variations such as“comprises” or “comprising”, will be understood to imply the inclusionof a stated element, integer or step, or group of elements, integers orsteps, but not the exclusion of any other element, integer or step, orgroup of elements, integers or steps.

SUMMARY OF THE INVENTION

According to a first aspect the present invention provides a method ofapplying a neural stimulus with an implanted electrode array, the methodcomprising:

-   -   using the electrode array to applying a sequence of stimuli        configured to yield a therapeutic effect while suppressing        psychophysical side effects, the stimuli sequence configured        such that a first stimulus recruits a portion of the fibre        population, and a second stimulus is delivered within the        refractory period following the first stimulus and the second        stimulus being configured to recruit a further portion of the        fibre population.

According to a second aspect the present invention provides a device forapplying a neural stimulus, the device comprising:

-   -   at least one electrode configured to be positioned alongside a        neural pathway, and    -   a control unit configured to apply a sequence of neural stimuli        which are configured to yield a therapeutic effect while        suppressing psychophysical side effects, the stimuli sequence        configured such that a first stimulus recruits a portion of the        fibre population, and a second stimulus is delivered within the        refractory period following the first stimulus and the second        stimulus being configured to recruit a further portion of the        fibre population.

By providing for a second stimulus to be delivered in the neuralrefractory period following the first stimulus, the present inventionprovides for de-correlated, or less correlated, fibre responses to beevoked by such stimuli.

The sequence of neural stimuli may comprise more than two stimuli, eachbeing delivered in the refractory period following a previous stimulusin the sequence.

The sequence of neural stimuli may comprise stimuli of ascendingamplitude.

The sequence of neural stimuli may be applied sequentially by a singleelectrode.

Alternatively, the sequence of neural stimuli may be appliedsequentially by more than one electrode. In such embodiments, the secondstimulus is preferably delivered at a time after the first stimuluswhich allows for cessation of the first stimulus and allows forpropagation of a first neural response evoked by the first stimulus fromthe first electrode to the second electrode, so that the second stimulusis delivered during a refractory period of neurons proximal to thesecond electrode after activation of those neurons by the evoked neuralresponse from the first stimulus.

Additionally or alternatively, in some embodiments the sequence ofneural stimuli may be applied by consecutive electrodes positioned alongan electrode array.

In embodiments where the sequence of neural stimuli is appliedsequentially by more than one electrode, the timing of the respectivestimuli in the sequence may be controlled in order to causespatiotemporal alignment of the respective evoked responses propagatingin a first direction along the nerve fibre to thereby cause correlationand summation of evoked responses in the first direction, while causingspatiotemporal misalignment of the respective evoked responsespropagating in a second direction opposite the first direction along thenerve fibre, to thereby decorrelate evoked responses propagating in thesecond direction. Such embodiments may be advantageous in decorrelatingevoked potentials propagating toward the brain, where it is desired toavoid or minimise any percept from the stimuli.

In some embodiments of the invention, the sequence of neural stimuli maybe followed by a single stimulus which is not applied during therefractory period of any preceding stimulus, and which is not closelyfollowed by any subsequent stimulus in the refractory period of thesingle stimulus. Such embodiments may be applied in order to enable anevoked response measurement to be made following the single stimulus, toenable ongoing refinement of stimulus parameters of the sequence ofneural stimuli.

According to a third aspect the present invention provides a computerprogram product comprising computer program code means to make acomputer execute a procedure for applying a neural stimulus with animplanted electrode array, the computer program product comprisingcomputer program code means for carrying out the method of the firstaspect.

According to a fourth aspect the present invention provides an automatedmethod of controlling a neural stimulus, the method comprising:

-   -   applying the neural stimulus as defined by a set of parameter        values;    -   measuring a neural response evoked by the stimulus;    -   comparing one or more characteristics of the measured neural        response to a desired response;    -   altering one or more of the parameter values; and    -   iteratively performing the applying, measuring, comparing and        altering, in order to explore a parameter search space having at        least two variable parameters, to identify a set of parameter        values which evokes a neural response best matching the desired        response.

According to a fifth aspect the present invention provides animplantable device for applying a neural stimulus, the devicecomprising:

-   -   a plurality of electrodes including one or more nominal stimulus        electrodes and one or more nominal sense electrodes;    -   a stimulus source for providing a stimulus to be delivered from        the one or more stimulus electrodes to neural tissue;    -   measurement circuitry for recording a neural signal sensed at        the one or more sense electrodes; and    -   a control unit configured to control application of a neural        stimulus as defined by a set of parameter values, the control        unit configured to measure a neural response evoked by the        stimulus, the control unit configured to compare one or more        characteristics of the measured neural response to a desired        response, the control unit configured to alter one or more of        the parameter values, and the control unit configured to        iteratively perform the applying, measuring, comparing and        altering, in order to explore a parameter search space having at        least two variable parameters, to identify a set of parameter        values which evokes a neural response best matching the desired        response.

The set of parameter values defining the stimulus may comprise one ormore of: stimulus current, pulse amplitude, phase duration, interphasegap duration, pulse shape, repetition rate, electrode selection andelectrode combination.

In preferred embodiments, the stimulus parameters are refined on anongoing basis in order to adaptively control the stimuli in response topostural changes of the user. In such embodiments, the parameter searchspace may be reassessed on a regular basis, for example once a second.Alternatively the parameter search space may be reassessed only inresponse to a trigger, such as a signal from an accelerometer which hasdetected patient movement, thereby avoiding excessive power consumptionat times when the patient is not moving.

In some embodiments of the invention, the one or more characteristics ofthe measured neural response may comprise a measure of neural fibreconduction velocity. In such embodiments, the measured neural fibreconduction velocity may be used to determine selectivity of recruitmentof a target fibre class, for comparison to a desired fibre classrecruitment ratio or range as defined by the desired response. Forexample for pain suppression the desired response may be defined asrequiring high selectivity of Aβ fibres.

Additionally or alternatively, the one or more characteristics of themeasured neural response may comprise a measure of neural responseamplitude. In such embodiments, the parameter search space may beexplored by iteratively applying stimuli and measuring neural responsesin order to identify a “perception” threshold for stimulus current,below which no evoked response arises from stimulus. Additionally oralternatively, such embodiments may explore the parameter search spacein order to identify a “maximum” or “comfort” threshold at a currentlevel above which a slow response first starts to arise, by assessingthe neural response amplitude at an expected time of occurrence of anyslow response, such as about 3-4 ms after stimulation.

In embodiments where the one or more characteristics of the measuredneural response comprise a measure of neural response amplitude, thestimulus parameters may be refined on an ongoing basis in order toadaptively control the stimuli in response to postural changes of theuser so as to maintain the evoked response amplitude at a fixed pointabove the perception threshold. Such embodiments may thus enable acontrolled level of neural recruitment even during user posturalchanges, and may also be of benefit in avoiding misalignment of inducedparaesthesia from a preferred location. To maximally align inducedparaesthesia with a preferred location, the stimulus parameters mayinclude a body map setting out the location of effects of stimuli whenapplied by each electrode of an electrode array. The body map may bepredefined and based on patient feedback to clinical trial stimuli, ormay be subject to revision during ongoing use for example by way of userinput upon a remote control of the implant.

In embodiments where the one or more characteristics of the measuredneural response comprise a measure of neural response amplitude, thestimulus parameters may be refined on an ongoing basis in order tomaintain stimuli at a sub-threshold level, for example as may beintended for non-paraesthesia therapeutic use.

In some embodiments, the one or more characteristics of the measuredneural response may comprise measures of variations of an amplitude of afast neural response in response to varied stimulus current. In suchembodiments, a comfort level threshold may be defined relative to aninflection point marking decelerating growth of the fast responseamplitude in response to increasing stimulus current. Such embodimentsrecognise that deceleration in the growth of the fast response amplitudein response to increasing stimulus current generally reflects wherefurther recruitment starts to fall and undesirable side effects beginsuch as onset or increase of a slow neural response.

In some embodiments, where the one or more characteristics of themeasured neural response comprise measures of variations of an amplitudeof a fast neural response in response to varied stimulus current, thestimulus may be maintained within a linear range of the neuralrecruitment vs. current curve, and an electrode-to-fibre distance d maybe estimated. An estimate for d may be obtained by measuring theamplitude (R_(e1p1), R_(e5p1)) of the neural response as measured at twospaced apart sense electrodes (denoted e1 and e5) for a first stimulus,and measuring the amplitude (R_(e1p2), R_(e5p2)) of the neural responseat the two sense electrodes for the same stimulus after a change in d.This embodiment recognises that despite a scaling factor S_(s) due tochanged measurement sensitivity with d, these measurements permit thechange in recruitment scaling factor A_(s) in response to d to becalculated as:

(R _(e1p2) /R _(e1p1))−(R _(e5p2) /R _(e5p1))=A _(s)

Additionally or alternatively, the electrode to fibre distance d may insome embodiments be estimated by obtaining neural response amplitudemeasurements in response to at least two stimuli of differing currentlevel, the stimuli being substantially within a linear range of theneural recruitment vs. current curve. Taking a linear extrapolation ofthe amplitude measurements to the x-axis (i.e. the point of zero neuralresponse) provides an estimate of the stimulus current threshold.

In embodiments obtaining an estimate of the electrode to fibre distanced, this estimate may be used to influence stimulus current and/or toappropriately scale measured neural responses to compensate for alteredmeasurement sensitivity, in order to maintain constant or controlledneural recruitment.

In some embodiments of the invention, the one or more characteristics ofthe measured neural response may comprise a measure of dispersion of theresponse relative to distance from the stimulus site. In suchembodiments, changes in dispersion may be used as indication of changesin electrode-to-fibre distance d, wherein increased dispersioncorrelates to increased electrode-to-fibre distance d.

In some embodiments of the invention, the one or more characteristics ofthe measured neural response may comprise a measure of fast neuralresponse peak position relative to stimulus. In some embodiments of theinvention, the one or more characteristics of the measured neuralresponse may comprise a measure of the fast neural response peak width.In such embodiments, the electrode-to-fibre distance d, and/or theneural recruitment efficacy, may be estimated by reference to peakposition and/or peak width of the fast neural response, with a fasternarrower peak reflecting greater recruitment and potentially a movementof the electrode towards the fibre.

In some embodiments of the invention, the one or more characteristics ofthe measured neural response may comprise a measure of spectralcharacteristics of the evoked response. In such embodiments, theelectrode-to-fibre distance d may be determined by reference to thespectral characteristics, recognising that a transfer function of anaction potential along a nerve fibre, and laterally to a senseelectrode, depends on d. For example, changes in d may be detected andestimated by selecting two different frequencies which are prominent inthe spectrum of the CAP, and examining the ratio between the twofrequencies overtime.

According to a sixth aspect the present invention provides a computerprogram product comprising computer program code means to make acomputer execute a procedure for automated control of a neural stimulus,the computer program product comprising computer program code means forcarrying out the method of the fourth aspect.

BRIEF DESCRIPTION OF THE DRAWINGS

An example of the invention will now be described with reference to theaccompanying drawings, in which:

FIG. 1 illustrates an implantable device suitable for implementing thepresent invention;

FIG. 2a shows the Aβ response amplitude growth functions for stimulationof the sheep spinal cord at 40, 80 and 120 μs, while FIG. 2b shows thecompound action potential recorded at equivalent charges for the threedifferent pulse widths;

FIG. 3 illustrates summation of a sequence of overlapped neuralresponses;

FIG. 4 is a schematic illustration of a potential pulse sequence and theamplitude growth curve associated with the sequence;

FIG. 5 illustrates ERT responses to bursts of stimulation with differingfrequencies;

FIG. 6 illustrates a stimuli scheme to generate stimuli which result insynchronising Aβ activation in the antidromic direction and adesynchronising activity in the orthodromic direction;

FIG. 7 illustrates experimental results obtained by applying a series offour stimuli of ascending amplitude on four adjacent electrodes to asheep spinal cord;

FIG. 8 illustrates experimental results obtained in response to stimulibursts of different inter-stimulus intervals;

FIG. 9 illustrates a suitable feedback controller for controlling theparameters of the stimuli burst in an automated manner;

FIG. 10 is a schematic of a typical biphasic charged-balanced stimuluspulse;

FIG. 11 illustrates a selection of pulse shapes which may be tested todetermine the most efficient at producing depolarisation;

FIG. 12 illustrates a set of stimulus parameters which may be controlledin accordance with the present invention;

FIG. 13 illustrates ovine compound action potentials resulting fromsuccessively applied stimuli of varying amplitudes, in order toascertain suitable threshold and comfort levels;

FIG. 14 plots measured spinal cord potential (SCP) amplitude arisingfrom biphasic stimuli of width 120 μs, each stimulus having a currentlevel in the range 0-4.5 mA, as measured in a human subject in a sittingposture;

FIG. 15 illustrates the two major response types in an evoked SCP;

FIG. 16 illustrates measured ovine evoked responses demonstrating fastand slow responses, together with an electromyogram (EMG) trace recordedfrom an electrode implanted in the corresponding muscle;

FIG. 17 is a schematic diagram illustrating the measurement of the peakto peak amplitude of the evoked neural response;

FIG. 18 is a schematic diagram of the neural response amplitude growthcurve relative to stimulus current;

FIG. 19 plots the amplitude of the “fast” and “slow” responses in ahuman subject while performing postural manipulations,

FIG. 20 is a schematic of a feedback controller to effect stimuluscontrol in response to recruitment of neurons;

FIG. 21 is a plot of a linear approximation of the SCP growth curve(evoked response amplitude vs. stimulus current), indicating therelationship between various threshold levels;

FIGS. 22a and 22b respectively plot the ascending and descending evokedCAP N1-P2 amplitudes each measured on four sense electrodes, recorded insheep with biphasic 40 us pulse widths

FIG. 23 illustrates respective SCP amplitude response curves, for twosense electrodes which are spaced apart along the spinal cord, and whichare at different distances away from the spinal cord;

FIG. 24 illustrates theoretical SCP amplitude response curvescorresponding to two different postures of the user, in order toillustrate SCP slope determination via a 2-point method;

FIG. 25 illustrates three SCP amplitude response curves measured from ahuman subject in three respective postures; and

FIG. 26 is an idealised representation of an SCP amplitude growth curveto illustrate salient features.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 illustrates an implantable device 100 suitable for implementingthe present invention. Device 100 comprises an implanted control unit110, which controls application of a sequence of neural stimuli inaccordance with the present invention. In this embodiment the unit 110is also configured to control a measurement process for obtaining ameasurement of a neural response evoked by a single stimulus deliveredby one or more of the electrodes 122. Device 100 further comprises anelectrode array 120 consisting of a three by eight array of electrodes122, each of which may be selectively used as either the stimuluselectrode or sense electrode, or both.

The activation and simultaneous suppression of different areas of tissueis highly desired for treatment of a number of neurological disorders.The activation of micturition or defection without contraction of thesphincter is highly desirable for treatment of incontinence. The goal ofstimulation of the spinal cord is to block transmission of pain signalsfrom Aδ and C fibres, via the inhibitory effect of the activation of Aβfibres. The ascending Aβ fibres produce a psycho-physiological responsewhich results in the paraesthesia (described as tingling by recipients).A number of ways to reduce or eliminate this effect have been suggested.It has been reported that burst mode stimulation or continuousstimulation at high frequencies can produce pain relief withoutaccompanying paraesthesia, however the mechanisms are not clear.

One possible explanation is that the high frequency stimulation resultsin a highly uncorrelated neural firing pattern in the ascending Aβtracts. High frequency stimulation results in the continuous activationof the fibres and produces a randomised firing pattern. The recoverytime (refractory period) between each fibre is slightly different and ifa depolarisation potential is present as the fibre comes out ofrefractory period, it will depolarise again, but not synchronised withother fibres which may still be in their refractory periods. The netresult is a randomisation of the firing pattern and a return of thestochastic response in the fibre.

Measurements of the evoked neural response provide a direct measure ofthe degree of correlation of the firing pattern. FIG. 2a shows the Aβresponse amplitude growth functions with respect to stimulus amplitude,for stimulation of the sheep spinal cord at 40, 80 and 120 μs. Therecruitment is related to charge and so stimulation at 1 mA for 120 μsproduces an equivalent charge for stimulation at 3 mA for 40 μs, withvertical lines highlighting two respective points of equal chargedelivery for each trace. FIG. 2b shows the compound action potentialrecorded at equivalent charges for the three different pulse widths. Thepeak height is smaller and the evoked response peak is wider at theequivalent charge for the longer pulse width than for the shorter pulsewidth, and this is indicative of a less correlated evoked response.

The probability of any single fibre responding is a function of theproperties and history of the fibre and the amplitude of the currentpulse. Although short and long pulses for an equivalent charge mayrecruit the same number of fibres the longer lower current amplitudepulse will recruit the fibres over a longer time scale than the highercurrent shorter pulse width.

Patients report a preference for stimulation with longer pulse widthsand the reason for this preference may be because the perceptual sideeffect is lower, because there is a lower correlation between the fibresfiring. Given this observation, highly uncorrelated responses may giverise to much lower psycho-physical side effects such as tinglingsensations and paraesthesia. The evoked responses measured for thelonger pulse widths are broader in FIG. 2b , indicating less correlationin the firing pattern.

Measurement of the evoked response provides a unique way to assess thedegree of correlation amongst fibres in a group, as the peak width andamplitude of the measured response directly relates to the degree oftiming synchronisation of the single fibre action potentials which sumto form the compound action potential. The goal of stimulus design is toachieve a high level of recruitment at the segmental level and a lowlevel of correlation for the ascending segments. The neural responsemeasurement obtained at each sense electrode may be conducted inaccordance with the techniques set out in Daly (2007/0225767), thecontent of which is incorporated herein by reference. Additionally oralternatively, the neural response measurement may be conducted inaccordance with the techniques set out in Nygard (U.S. Pat. No.5,785,651), the content of which is incorporated herein by reference.Additionally or alternatively, the neural response measurement may beconducted in accordance with the techniques set out in the Australianprovisional patent application filed simultaneously herewith in the nameof National ICT Australia Ltd entitled “Method and apparatus formeasurement of neural response”.

The degree of correlation within an evoked response can be measured withsuch techniques, and pulse sequences can be designed to produce evokedresponses of a desired character. A typical recruitment curve is shownin FIG. 2a . The strength of the Aβ potentials directly relates to thenumber of fibres recruited, and therefore stimulation at successivelarger and larger pulse amplitudes will recruit successively morefibres. If the pulses are timed so that they occur within the refractoryperiod of the excited neurons from the previous pulse then different subpopulations of neurons can be selected with each pulse.

The timing of each pulse can be so arranged so that the travelling CAPsfrom each individual pulse cancel each other as they sum at somedistance from the stimulation site. This indicates the degree ofdesynchronisation between the fibres, and as the sensory input is basedon correlation of firing patterns the sensation (paraesthesia) isreduced. However, the activation of the inhibitory effect of the Aβfibres at the segmental level is not reduced, permitting Aβ inhibitionof Aδ and C propagation to occur, as desired.

FIG. 3 illustrates the principle of applying a sequence of neuralstimuli and allowing the respective evoked responses 302, 304, 306 topropagate along the fibre. The numerical summation of five suchpartially overlapping compound action potentials, of which only threeappear in FIG. 3, is shown at 308. FIG. 3 shows the effect of thesummation of the evoked response from five pulses with the timingintervals between the pulses so arranged as result in the arrival of theevoked response waveform at a designated point along the electrode arraysuch that the averaged signal recorded at that point is minimised. Forthe data shown in FIG. 3 the timing difference between each cathodicpulse is 0.3 ms.

FIG. 4 is a schematic illustration of a potential pulse sequence (lower)and the amplitude growth curve associated with the sequence (upper).Current levels A-C are represented on both portions of FIG. 4. Theinitial pulse of amplitude A can be expected to recruit only a portionof the available population. Application of the subsequent stimulus ofgreater amplitude can then be expected to recruit a further portion, butnot all, of the available neural population, even though stimulus B isapplied during the refractory period after stimulus A. Similarly,stimulus C can be expected to recruit a further portion of the availableneural population. C may be applied during the refractory period ofstimulus B only, or possibly within the refractory period of bothstimuli A and B. The sequence of neural stimuli A-B-C can thus beexpected to recruit perhaps a similar amount of the available neuralpopulation as would stimulus C if applied alone, however the progressiverecruitment of portions of the neural population at progressive timesprovides for a significantly decorrelated evoked response as compared tothe response resulting from a single stimulus of amplitude C.

The concept of a selection of stimulus sequences based on the ERTrecorded parameters can be greatly extended. For instance the example ofFIG. 4 demonstrates achieving an uncorrelated ensemble response in thefibre population being stimulated.

FIG. 5 illustrates ERT responses to bursts of stimulation with differingfrequencies. The degree of correlation can be inferred from the ERTsignal. A normal stimulus can be used to assess the stimulation responseamplitude in the absence of any further desynchronising pulses. Theamplitude of the single probe pulse is adjusted to represent the totalcharge delivered over time for the corresponding desynchronising pulsetrain. The amplitude of the response measured from the single probepulse represents a fully synchronised response. The desynchronisingpulse train is then output and the response measured. The ratio of thetwo responses is proportional to the level of synchronisation and so canbe used as a control parameter for adjusting the characteristics of thedevice. For instance the control parameter may be adjustable by thepatient to allow the patient to adjust the level of perceivedparaesthesia. The control variable may also be used by the system fordetection of a change of state in the neural tissue for a diagnosticpurpose.

A single non-decorrelating stimulus can be applied to the nerve by thedevice periodically or occasionally in order to elicit an evokedresponse which is then used as the input to the control loop. This probestimulus can be adjusted so that its charge is equivalent to the chargepresented by the desynchronising stimuli. The frequency of the probepulse to desynchronising pulses can then be adjusted to minimise theperceptual side effects. The probe frequency can also be adjusted ondemand, responding more rapidly to changes in movement, for example.

Conduction of the compound action potentials occurs both orthodromically(up the spine) and antidromically (down the spine). Careful choice ofstimulus design can be used to create a situation where the degree ofsynchronisation can be different in both directions, and controllablyso. For example it may be desirable to generate stimuli which result insynchronising Aβ activation in the antidromic direction and adesynchronising activity in the orthodromic direction. One possiblescheme for doing this is illustrated in FIG. 6. A stimulus pulse,preferably biphasic, is discharged at an electrode (electrode ‘0’indicated on the left side of FIG. 6). At some time interval later a2^(nd) stimulus pulse is discharged between another two electrodes. Forconvenience this is illustrated in FIG. 6 as the electrode (number “1”)adjacent to the first electrode. The 2^(nd) discharge is arranged sothat it occurs in time and place such that its resultant CAP propagationto an electrode (e.g. ‘+6’) in one direction (the upward direction inFIG. 6) sums with each other evoked CAP. In contrast, in the otherdirection (the downward direction in FIG. 6), the respective CAPs aremisaligned and decorrelated for example when observed at electrode ‘−3’.

A possible means but not the only means to achieve such directionalselectivity of CAP correlation is to arrange a series of stimulus pulseswith an interpulse interval equal to the difference in propagation timerequired for desynchronisation of the CAP in the ascending direction.

Note that the order in which the stimuli are presented does not need tobe sequential. The amplitudes of the individual stimuli can also bevaried according to the scheme of FIG. 4. The timing of presentation canalso be dithered to adjust the timing.

FIG. 7 illustrates experimental results obtained by applying a series offour stimuli of ascending amplitude on four adjacent electrodes to asheep spinal cord. Each stimulus was a tripolar stimulus for which therespective centre electrode was, in order, electrode E7, E8, E9 and E10,being the four centrally positioned electrodes of a 16 electrode linearelectrode array. Each stimulus was biphasic with each phase having apulse width of 20 μs, and the interphase gap being 10 μs. The stimuliwere of ascending amplitude, being 2 mA, 2.5 mA, 3 mA and 3.5 mArespectively. The inter-stimulus interval between each successive pairof stimuli on the respective electrodes was 33 μs, so that thepulse-to-pulse time was 83 μs, to optimally correlate the net evokedresponse in the antidromic (ie caudal) direction. As can be seen in FIG.7 the antidromic response 704 measured on electrode E16 was wellcorrelated from the four constituent parts, and is of large amplitude.In contrast, the four orthodromic responses were effectivelydecorrelated and produced a net response 702 measured at electrode E3which was of much reduced amplitude compared to response 704 travellingin the opposite direction, even though both were produced by the sameburst of four stimuli.

FIG. 8 shows the responses measured at different inter-stimulusintervals. As can be seen the inter-stimulus interval strongly affectsefficacy of this technique, and so preferred embodiments provide afeedback loop in order to optimize this parameter, and all otherstimulus parameters, in setting up the stimuli burst. FIG. 9 illustratesa suitable feedback controller for controlling the parameters of thestimuli burst in an automated manner, so as to use the measured evokedresponses in each direction to determine the stimulus parametersrequired to achieve a desired directional effect. Such automatedfeedback permits the relatively large parameter space to be efficientlyexplored to identify optimal stimuli burst parameters.

Improvements in efficiency and recruitment selectivity are highlydesirable. There have been two major types of stimulus waveforms used togenerate propagating action potentials: voltage control and currentcontrol. Current control pulses are normally biphasic—current is passedfrom one electrode to another in the system, and then reversed. Atypical biphasic charge-balanced stimulus pulse has an amplitude (A) andwidth (t) with an interphase gap Ø, as shown in FIG. 10. Such a pulseapplied to the spinal cord produces an evoked response. The strength ofthe evoked response is related to the neural recruitment, and the shapeof the evoked response is related to the distribution of fibre typesbeing recruited. Considering the parameters A, t, Ø, it is possible toadjust these parameters in a systematic manner so as to obtain a desiredevoked response output.

Moreover, the present invention recognises that non-rectangular pulseshave an effect on the strength-duration relationships of recruitment.FIG. 11 illustrates a selection of the many different possible stimuluspulse shapes which may be tested to determine which is most efficient atproducing depolarisation. The strength-duration curve relates the timefor which a stimulus is applied to the nerve, to the recruitment levelof the fibres in the nerve. The temporal recruitment responses fordifferent fibres of different sizes depend on the pulse shape. A largenumber of large diameter fibres are recruited at the beginning of asquare pulse (FIG. 11a ), and an approximately constant uniform numberof small fibres are then recruited over time as the pulse continues. Incontrast, negative sloping waveforms (FIGS. 11c, 11e ) recruit highnumbers of both large and small diameter fibres. The adjustment ofstimulation parameters for a spinal cord stimulator requires recruitmentof Aβ fibres. Recruiting smaller fibres such as Aδ fibres may causeundesirable side effects.

If there is a wide range of different fibre diameters being recruitedthen the (N₁ ^(t)-P₂ ^(t)) will spread out as the action potentialpropagates up the spinal cord. This is because as disparate fibreclasses are recruited, the P-N-P morphology of the CAP is replaced by amore complicated waveform, which can generally be thought of asequivalent to the summation of one P-N-P wave per fibre class.

There are thus two salient parameters which may be focused upon. First,the strength (amplitude) of the evoked response, which relates to therecruitment. Second, the evoked response dispersion which relates to theselectivity of fibre classes.

The present invention recognises that there are a number of ways toadjust the stimulus parameters (such as stimulus shape and amplitude) inorder to optimise the selectivity and efficiency of recruitment.However, the past approach of optimising a stimulus on the basis ofpatient feedback is entirely impractical when the parameter search spaceis made so large as to include pulse shape, amplitude, interphase gap,and so on. Accordingly, to search for an optimally efficient set ofstimulus pulse parameters, the present embodiment provides for automatedoptimisation of the stimulus pulse parameters based on measurement ofthe evoked response arising from test stimuli having varied stimulusparameters. The stimulus optimisation process in this embodiment occursautomatically, and may be completed within minutes and thereforeperformed regularly, as opposed to clinical optimisation.

There are a number of ways to adjust the stimulus parameters. In thepresent embodiment, the stimulus parameter search space is explored byiteratively applying stimuli and obtaining measurements of neuralresponses thereto, assessing how well the measured response confirms toa desired response, and refining the stimulus parameters in accordancewith a genetic, heuristic or other search algorithm. A geneticalgorithm, for example, may separate the parameter set into two sets oftraits, and iteratively modify the contents of each set, whereby eachiteration combines the traits of the more successful parameter values toform a new set of parameters for stimulus application.

The present embodiment thus permits a considerably more generaliseddefinition of the stimulus, as shown in FIG. 12. In this embodiment,parameters which are varied within the parameter search space include:

Amplitude A₁, A₂, A₃, A₄ which are the amplitudes of the various peaks.Pulse period P₁, P₂ the duration of the pulses. Interpulse g the gapbetween the first pulse and gap the second pulse. Pulse F₁(t) and F₂(t)define the shape of each phase function Frequency f determines therepetition rate for the stimulus

For example, a pure sinusoidal response can be generated with f(t) as asin function g=0, A2=A3=0. A conventional square biphasic pulse has aparameter set F₁(t)=−F₂(t)=A1=A2=−A3=−A4.

FIG. 13 illustrates measured ovine compound action potentials, whicharose in response to successively applied stimuli of varying amplitudes,in order to ascertain suitable threshold and comfort levels. Thestimulus pulse width was 40 μs. FIG. 13 illustrates that stimulus pulseamplitude can be progressively varied in order to determine a stimulusamplitude at which the greatest fast response is evoked, with the leastslow response.

By iteratively refining the stimulus parameters and applying differingstimuli under control of a suitable search algorithm e.g. a geneticalgorithm, the stimulus parameter search space can be effectively andswiftly explored to identify a specific set of values for the stimulusparameters which best generate a desired evoked response. There areseveral parameters that are useful to optimise for the individual. Thetotal charge delivered per stimulus pulse determines the powerconsumption of the device and hence the time between recharges for arechargeable device or the lifetime of the device for a non-rechargeabledevice. The pulse parameters, duration of the inter-phase gap etc, canbe varied and the combination which delivers the desired evoked responsefor the minimum delivered charge can be determined by application of asuitable search technique.

The present invention may further provide for partly or completelyautomated device fitting. The amplitude of the evoked response providesa measure of the recruitment of the fibres being stimulated. The greaterthe stimulus, the more recruitment and the larger the evoked response. Aplot of the compound action potentials measured in a sheep spine for anumber of stimulus amplitudes is shown in FIG. 13. The peak heightvaries with the amplitude of the applied stimulus in a consistent (i.e.monotonically increasing) way.

FIG. 14 plots measured spinal cord potential (SCP) amplitude arisingfrom biphasic stimuli of width 120 μs, each stimulus having a currentlevel in the range 0-4.5 mA, as measured in a human subject in a sittingposture. At some amplitude the patient experiences a sensation derivedfrom the stimulus (at a current of 2.75 mA in FIG. 14). The perceptionthreshold corresponds to the appearance of an evoked response. There area number of factors which can influence the amplitude of the responsegenerated by a fixed set of stimulation parameters.

The evoked response for the Aβ fibres can be used in a number of waysduring the implantation and subsequent programming of the device. Theseinclude:

1. Determining the optimal combination of electrodes to generate thedesired therapeutic effect;

2. Selection of the stimulus parameters to generate the desiredtherapeutic effect;

3. Continuous adjustment of the stimulus parameters to remove variationsin recruitment induced by movement, or relative movement of the spinalcord with respect to the electrode position, and

4. Minimisation of stimulation side effects

Very often during the assessment of patient suitability for spinal cordstimulation, a trial period is undertaken during which an electrode istemporarily implanted in the epidural space above the spinal cord. TheCAP measures of the present invention can be recorded during thisimplantation and may provide sufficient diagnostic indicator ofneurophysiological response to warrant the surgeon performing an implantof the full system.

The evoked response recorded from the epidural space in the spinal cordvaries with the stimulus amplitude and has two components at highamplitudes. It consists of an immediate response (short durationcharacteristic of the response from fibres with a high conductionvelocity), followed by a response with a much longer time scale. Theshorter response is characteristic of the recruitment of Aβ fibres inthe dorsal column. The response which occurs at longer time scalesinvolves motor system neural responses, EMG, etc. These signal featuresare shown in FIG. 15.

The normal clinical procedure for adjustment of spinal cord stimulationparameters involves adjustment of pulse width, current and rate to placean induced paraesthesia over the site of pain. There is an upper limitto the intensity of the stimulation, beyond which the patient will notaccept further increases, referred to as the dose limit. For somepatients this point also corresponds to the point where effectiveparaesthesia is present and there is good pain relief, however for some,the side effect of the stimulation is intolerable for the patient.Overstimulation of Aβ fibres is also unpleasant for the recipient andunfortunately results in poor efficacy because, although good coverageis obtained, the patient cannot take benefit from the treatment becausethe side effects are too severe.

The fibre types that are responding at the dose limit have been assessedfrom patient feedback of the sensations induced. Selected resultsinclude:

-   -   56% of patients reported the sensations which are typical of Aβ        responses.    -   15% reported Aδ typical sensations.    -   6% reported C fibre responses.    -   21% reported sensations corresponding to motor muscle spinal        responses.

The Aβ fibres are large in diameter (13-20 μm) and much larger than Aδfibres (1-5 μm) and C fibres (0.2-1.5 μm). The C fibres have the slowestconduction velocity 0.5 to 2.0 m·s⁻¹ whereas Aδ fibres have conductionvelocity of 3-30 m·s⁻¹.

Considering the propagation velocity of recruited Aδ fibres ascendingthe spinal cord is m·s⁻¹, and a typical distance of a spinal cordelectrode array is 7 cm long, the propagation delay from one end of theelectrode array to the other is 4.6 ms.

FIG. 16 illustrates the evoked response in a sheep spinal cord,demonstrating fast and slow responses. The black dotted line is anelectromyogram (EMG) trace recorded from an electrode implanted in thecorresponding muscle. The Aβ activity is present in the 0 to 1.5 ms timewindow. Above a threshold stimulation current level, a slow response isobserved 2 ms after stimulation. The slow response is the result of theactivation of other neural elements. Activation of the Aδ fibres resultsin activation of the spinal reflex loop (nociceptive reflex) and cancause muscle contractions. Direct activation of motor neurons also willcause motor responses. Observation of the slow responses in animalexperiments was accompanied by the observation of muscle twitching,while observation of the slow response in humans is observed only atuncomfortable stimulation levels.

The present embodiment thus recognises that evoked response measurementssuch as those of FIG. 15 can be used to determine the allowable dynamicrange of stimulation which is available to the patient. In thisembodiment, the presence of the slow response is automatically detectedby the implanted device, by looking for an evoked response which has apeak from around 3 to 4 ms after the start of stimulation. The slowresponse is an indicator of the recruitment of fibre classes other thanthe target Aβ fibres and is accompanied by side effects which areundesirable. The dynamic range available to the patient can bedetermined by using the onset of a slow response as an indication of anupper limit to the stimulation settings. The slow response can bebrought on and measured either during normal use of the device or undergeneral anaesthesia, by adjusting the stimulus level until the slowresponse characteristic emerges in the measured neural response,indicating that the comfort threshold has been reached. This procedurecan be conducted on each electrode of the array, various combinations ofelectrodes, and in a number of different postures of the patient. Amaximum safe stimulation level may then be set in the patient'scontroller for each electrode.

An alternative measure of the patient's posture (e.g angle detection viaa triaxial accelerometer) may be used to select the slow responsethreshold. Alternatively, an algorithm may be implemented in the implantwhich simply looks for the presence of a slow response and reduces theoutput of the stimulator should a slow response be detected.

Another embodiment provides for measurement of a stimulation thresholdand creation of a percept body map. The stimulation threshold for neuralrecruitment can be determined from the peak to peak amplitudes of thefast response. It corresponds to the minimum stimulation level requiredto produce a psycho-physical sensation. One difficulty faced inprogramming any neuromodulation system is to determine the locus ofstimulation on a perceptual body map. This is because, in existingsystems, there is no way to standardise the stimulus such that itproduces a constant level of recruitment. Varying the stimulus amplitudehas an effect on both the locus of the perceived stimulation and on thearea covered. Stimulating at fixed point above threshold (n.T_(e)) forthe Aβ fibres allows stimulation at fixed level of recruitment. Anaccurate body map relating percept with electrode stimulation locationcan be determined by stimulating each electrode in turn and asking thepatient to locate the locus of perception on a graphical body map. Thethresholds can be determined for single electrodes as stimulating sites,or for two electrodes used in parallel as a single site, or any otherapplicable combination of electrodes.

A body map based on threshold or other constant recruitment condition isa useful reference for device control, as it provides a method to selectelectrodes to achieve the desired level of coverage.

Currently, the task of a clinician programming such a system is tooptimise the pain relief by selecting stimulus parameters and locationto achieve coverage, i.e. matching the area of paraesthesia with thearea over which the patient experiences pain. The choice betweenstimulating at one or two locations can have an impact on the powerconsumption of the system. Mapping the percepts at constant Aβ evokedresponses allows the clinician and user to quickly identify electrodeswhich are aligned with the regions required for pain relief. Thedifferences in percept for different combinations of electrodes providea guide for lowering power consumption. For example, where twoelectrodes correspond to the same paraesthesia location, thenstimulation on those two together will reduce the power consumption ofthe device.

Yet another embodiment provides for stimulation below the threshold atwhich paraesthesia is perceived. There are a number of therapeuticbenefits obtainable from spinal cord stimulation. For example spinalcord stimulation has been used to treat chronic peripheral vasculardisease, in which the mode of action appears to be stimulation of thesympathetic nervous system. Spinal cord stimulation has also been foundto be effective in the treatment of chronic leg ulcers. The control ofstimulus parameters is complex in this clinical condition. The clinicianis not necessarily aiming to produce a paraesthesia in order to generateclinically therapeutic stimulation of the sympathetic nerves. However,in conventional SCS systems, the only indicator that stimulus parametersare producing neuronal depolarisations is through the patient reportingthe presence of a paraesthesia. The present embodiment, using neuralresponse measurements, provides a method to objectively quantify thestimulation threshold and may thus permit effective use of sub-thresholdstimuli. Using this threshold and its potential variations due toposture, a stimulus parameter can be selected which is belowpsychophysical threshold, so that continual excitation can be achievedwhich is below sensation threshold, and independent of posture.

In another embodiment, the fast response is measured to set the comfortlevel without reference to the slow response and indeed possibly withoutever causing a slow response. The recorded electrically evoked compoundaction potential is the sum of a multitude of single fibre evokedresponses, and its strength represents the level of recruitment of thefibres (i.e. the size of the signal is proportional to the number offibres responding to the stimulus). A convenient way to represent thisis to measure the peak to peak amplitude of the response (C-B in FIG.17).

The amplitude growth curve for the peak to peak response is readilyobtained by measuring the responses at different stimulus parameters(pulse width and current level). The charge on the electrode generatesequivalent responses independent of the pulse width. The fast responseamplitude growth curve, as illustrated in FIG. 18, can be used to setthe comfort level (the level beyond which unwanted side effect stimuliwould result), simply by inspection of the growth curve. This embodimentmay thus avoid the need to deliberately induce a slow response in orderto ascertain the comfort threshold. The stimulus needs to be maintainedaround or below the point A indicated in FIG. 18. Increasing the currentabove this point results in no further desirable recruitment and itpotentially results in a generation of unwanted or unpleasant slowresponses. Point A may be estimated from the amplitude measurements byfinding an inflection point in the growth curve, or by noting a reducinggradient of the curve, for example.

Electrode to electrode variation in stimulus thresholds may indicatedifferences in proximity of electrode to the spinal cord, or that theelectrode may be adjacent to neural regions of greater sensitivity. Theprocedure to locate the ideal electrodes for stimulation efficiency isto create an electrode sensitivity map. This is obtained simply byperforming a stimulus current sweep on each electrode, while obtainingneural response measurements at each level, so as to obtain the evokedresponse amplitude vs. stimulus current curve, for all stimulatingsites.

Further embodiments of the invention provide for estimation of thespinal cord-to-electrode distance. In order to maintain a constant levelof recruitment, it is necessary to estimate the evoked neural responselevel arising from a particular stimulation. Given that one of theprimary factors affecting recruitment efficacy is relative motionbetween the spinal cord and the electrodes, it is extremely useful toestimate the cord-electrode distance.

In another embodiment for estimating the cord-to-electrode distance, therelationship of the evoked SCP to the stimulation is exploited. Forsimple stimulation in the linear region of the amplitude growth curve,recruitment varies with the number of fibres for which the activatingfunction (the axial second derivative of voltage) is above threshold. Itcan be shown that, in a homogeneous volume conductor (HVC), theactivating function varies with 1/d². Hence, for a fixed stimuluscurrent in a HVC, the recruitment varies approximately with 1/d². Thisembodiment also recognises that, in measuring the SCP, twodistance-related factors are prominent. Due to the nature of the fibre,having discrete nodes of Ranvier easily modelled as a line of pointcurrent sources, the SCP amplitude in a HVC varies with 1/d² (as well aswith fibre diameter). This means that in the linear region of theamplitude growth curve, the combined effect of recruitment sensitivityto d and measurement sensitivity to d causes the measured SCP amplitudeto approximately vary with current*1/d²*1/d², or current/d⁴. Based onthis recognition, this embodiment therefore applies an algorithm whichuses probe stimuli in the linear range (between threshold and onset ofsaturation), to estimate the cord distance relative to some calibrationvalue. Hence, the recruitment can be estimated for a particularstimulus, relative to some calibration point.

In another embodiment of the invention lateral movement of an electrodeis monitored and estimated. This embodiment recognises that anecdotaldata from sheep experiments, as well as a consideration of spinal cordanatomy, suggests that as the epidural stimulation site shifts laterallyfrom the midline, the chance of eliciting motor reflexes and otherresponses of the motor neurons increases. For a given stimulusintensity, if the slow responses appear or become larger thanpreviously, this is an indicator that lateral movement of the electrodehas occurred. This scenario may lead to undesired sensation and may needto be rectified. In such embodiments a paddle electrode may be used,comprising multiple columns of electrodes, and then the selection ofstimulation electrodes may be changed such that the new stimuluselectrodes are medial of the previous off-centre stimulating electrodes.If a single “percutaneous” electrode array is used, the stimulusintensity may be reduced to avoid the undesired sensation produced, oragain the stimulus location may be shifted.

Embodiments of the invention may be applied only occasionally, forexample only in a clinical setting. Alternatively, automated neuralresponse measurements in accordance with the various embodiments of theinvention may be used regularly, or even substantially continuously toadjust the system in real time.

Yet another embodiment of the invention may obtain measures of both theneural response and also electrode impedance as measures of activity foradjustment of the system. The evoked response measurements are sensitiveto the distance between the excited neural tissue and the senseelectrode. Variations in the position of the electrode affect both thelevel of recruitment and also the strength of the measured evokedresponse due to the losses of the electric field propagating in themedium. The variation in the evoked response which is induced byrelative movement of the electrode and spinal cord can be used to detectactivity and movement of the recipient.

Many recipients of spinal neuromodulators report discomfort or changesin modulation with movement. The evoked potential change could be usedto control the stimulus current in a “tight” feedback loop or in a“loose” feedback loop, in order to avoid the stimulus from causingdiscomfort when the user moves or changes posture. In a loose feedbackloop, the evoked response could be used to control the stimulus betweensay two values, a first setting used for ambulatory periods or periodsof activity, and a second setting used for periods with relativelystable evoked response measures. A useful example may be the detectionof periods of sleep (relatively low movement) where it would bedesirable to turn down the amount of stimulation to conserve batterylife during periods of rest. Alternatively, during periods of highactivity it may be preferable for the implantee to receive a lowertherapeutic (or no therapeutic stimulation) to lower the likelihood ofunwanted undesirable stimulation.

In this embodiment, changes in movement are detected and the pattern ofthese changes is used to control device parameters. In addition toadjusting the stimulus level, this embodiment adjusts other deviceparameters which have an impact on the operation of the system. Notingthat continuous recording of the evoked potential consumes additionalelectrical power, this embodiment further controls the rate at whichmeasurements are obtained in response to the level of activity. Thelevel of implantee activity may also be logged by the system and used asa measure of the performance of the system in achieving pain relief.

In embodiments addressing postural changes, a further issue arises inthat gross posture alone (as might be measured by an implantedaccelerometer) may not sufficiently indicate the appropriate parameters.FIG. 19 provides plots of the amplitude of the “fast” and “slow”responses in a human subject while performing postural manipulations.The posture or relative position of the stimulator gives informationabout the position of the stimulator. However, in the “fast” curve ofFIG. 19 the stimulation efficiency changed when the patient was lying ontheir back and asked to bring their knees to their chest. Although thestimulation efficiency and patient's perception change significantly, animplanted accelerometer would not have been able to sense these posturalchanges because the device remains at the same orientation. In contrast,neural response measurements can be used to greatly improve theeffectiveness of neurostimulator adjustment when combined withaccelerometer measurements of posture. Simultaneously recording neuralresponses and measuring posture with an accelerometer can be used in anautomated process to determine the appropriate parameters for theneurostimulator for a wide range of postures. Notably, such simultaneousrecording does not necessarily require implantation of a device equippedwith neural response recording capabilities, as it can be performedduring the trial stimulation phase when patients have been implantedwith an externalised lead.

In such embodiments utilising simultaneous neural response measurementsand accelerometer posture measurements, determining the patientparameters comprises:

1. the neural response measurement system is used to record responsesunder an initially programmed set of conditions.

2. The patient changes posture and the posture is measured viaaccelerometer and responses recorded at the new posture.

3. Adjustments are made to the stimulus parameters based on the evokedresponse measurements. The adjustments are made to bring the neuralresponse measure equal to the first neural response measure, preferablyaccounting for varying measurement sensitivity arising from a changedelectrode-to-fibre distance d. Note that the adjustments can be doneautomatically in a feedback loop.

4. A table of program parameters versus posture parameters is updatedwith new posture data and program data determined from the neuralresponse.

The process outlined can use any or all of the feedback techniquesdescribed herein to adjust the stimulation parameters automatically. Inthis way programming of the device for different posture settings issimply a matter of setting up the process as described and asking thepatient to vary their posture. This could be done over days, for exampleduring the trial stimulation period, improving data quality. Anindicator could be provided to give feedback to the patient on thepercentage of possible posture variations as determined by the range ofthe measurement device.

Another advantage of the system as described is the ability to identifypostures for which there are ambiguous stimulation parameters; forexample, supine with straight legs versus supine with knees to chest.Continuous recording of both posture and feedback parameters based onneural response measurements may allow identification of posture valuesfor which there are two or more different stimulation parameters. Ifused without neural response measurements, the patient parameter setchosen from an ambiguous parameter set could be the set corresponding tothe lowest stimulation current, thus preventing unwanted side effects.

Neural response measurements conducted during a trial stimulation periodmay be used to create a table of parameters for use withaccelerometer-based implants. Neural response measurements can also beused continuously with accelerometer-based measurement. An accelerometeror simple passive movement detection could be used as an indicator ofactivity. Neural response measurements consume power and so the rate atwhich they are obtained will have an impact on the battery life of thesystem. It is highly desirable to manage the rate of measurement (andhence the power consumption). An accelerometer or passive movementdetector could be used to detect movement of any type, in response towhich the neural response measurement sample rate may be adjusted up ordown, so that the response is optimally adjusted with the minimum numberof neural response samples acquired.

Employing neural response measurement in a neuromodulation system leadsto a variety of available mechanisms for improving the therapeuticoutcome of SCS implantees. Discussed below are various controlalgorithms based on neural response feedback signals. It should be notedthat all of these feedback mechanisms may be enabled only when movementis detected, since this is when the stimulus needs to be updated tooptimise the pain relief. Enabling feedback control only when movementis detected may also lower the overall power consumption of the implant.Detection of movement may be achieved in a number of ways, including:monitoring via ball-in-tube type detectors, accelerometers, gyroscopes,etc.

In order to maintain a constant level of analgesia, it is desirable torecruit enough of the appropriate dorsal column fibres, while avoidingrecruitment at levels or in areas associated with side effects. Controlof recruitment can be achieved by varying any one of several parameters,such as current or pulse-width. However, when modulating a singleparameter, patient discomfort can limit the range of conditions underwhich recruitment can be held constant. For example, as currentincreases, fibres lateral to the electrode are more likely to berecruited. Thus, instead of controlling one parameter at a time, it ispossible to control several. The choice of parameters is made tominimise discomfort and stimulation energy for any desired stimulationcommand (up to some programmed limit). FIG. 20 is a schematic of such afeedback controller based on recruitment of neurons.

The simplest implementation is a piecewise specification of stimulationparameters from the command. For example, if we specify that theinjected charge should be proportional to the command value:

-   -   [[FIGURE—PW/I vs. Command]]

The Command generated is a value which is proportional to the error inthe recorded response (ie the difference between the set point and themeasured response). The parameter selector can select any parameter toadjust (pulse width, current level, frequency of burst etc). One simpleoption is to make the charge delivered proportional to the command valuewhich reduces the feedback loop to a simple proportional control loop.

The optimal command-to-stimulus mapping depends on factors includingspinal geometry, control loop parameters and desired performance, andthe psychophysical requirements of the individual patient. Thus it maybe necessary to select between different parameter-selection algorithmsdepending on external factors, such as movement detection or patientcontrols.

FIG. 21 is a plot of the SCP growth curve (amplitude vs current),indicating the relationship between various threshold levels: Tf, thethreshold for fast response; Ts, the threshold for slow response; andTt, the threshold for therapeutic response. For automated feedbackcontrol, the therapeutic stimulus level is initially set at some pointbetween Tf and Ts. For the initial setting an initial ratio isdetermined which places Tt between Tf and Ts.

Tt−Tf=Rt

Tf−Ts

Then for any subsequent stimuli

Tt=Ri*(Ts−Tf)+Tf

The stimulus which is used to probe the slow response presence orabsence is output at frequency which is not annoying to the recipient.The fast (<2 ms) response recorded is due to activation of Aβ fibres inthe spinal cord, and the slow response observed accompanies unwanted,uncomfortable or undesirable stimulation (e.g. muscle fibre activation).Thus, the stimulus level should ideally be set between the fast responsethreshold value (Tf in FIG. 21) and the value at which an unwantedresponse is evoked.

An algorithm can be defined which is based on the presence or absence ofAβ and slow responses, as follows:

1. A stimulus Sp (=Tf+ΔTs) targeted to be less than the therapeuticstimulus but greater than threshold Tf is used to evoke a response.

-   -   a. If a response is detected in <2.0 ms then do nothing else.    -   b. If no response is detected, increment the threshold Tf by an        increment ΔTs

2. A stimulus SL (=Ts−ΔTs) targeted to be greater than the therapeuticstimulus but less than that required to elicit a slow response is output

-   -   a. If a slow response is detected, decrement the threshold Ts by        ΔTs    -   b. If a slow response is not detected, then do nothing.

3. The therapy setting is calculated as a ratio of the differencebetween the thresholds Tf and Ts.

Embodiments of the present invention may further give an estimation ofconstant neural recruitment. The electrically evoked compound actionpotential is a measure of the level of excitation of nerve tissue beingexcited. The ECAP is the result of the summation of single fibre actionpotentials from a large number of fibres. The ECAP magnitude depends onthe number of fibres and their distance from the sensing electrode.Fibres which are far away from the sense electrode will contribute lessto the ECAP due to the strength of the coupling between the senseelectrode and the fibre.

Neuromodulation is used to describe the electrical stimulation of tissuein order to produce a therapeutic effect. Passing a current through thetissue and generating action potentials to produce the therapeuticoutcome. The number and strength of action potentials in response to thecurrent is not always proportional to current and depends on a number offactors:

-   -   The refractory period of the neurons in the nerve    -   The temperature    -   The distance from the electrode to the nerve

There can be large shifts in the level of recruitment with changes inseparation between electrode and tissue, indeed such shifts can takestimulation parameters from sub threshold to above the therapeuticbenefit range. This occurs frequently with spinal cord stimulators wherean electrode is implanted in the epidural space and the stimulationtarget is near the dorsal horn of the spinal cord. The separationbetween the electrode and the target tissue varies with changes inposture. To address this, embodiments of the present invention maymeasure the strength of the evoked response and use this as the feedbackpoint for control of the stimulus levels. The measured ECAP potential isproportional to the level of neural recruitment and a scaling factorwhich relates to the separation (and intervening tissue properties) ofthe sense electrode from the neural elements. In order to generate atarget value in order to perform the feedback control, the variation ofthe signal due to the separation from the electrode must be removed.

The present invention presents a number of methods by which to extractthe level of recruitment of the underlying tissue, independent of theseparation of the sense electrode. The evoked response recorded for theAβ fibres from the spinal cord is illustrated in FIG. 14. The amplitudeof the response can be characterized by the P2-N1 peak, the N1 peakalone or by the P2 peak alone.

A first embodiment for estimating recruitment in the presence of varyingelectrode-to-fibre distance d, is based on relative amplitudes found inmeasurements at two electrodes. The amplitude of the evoked responsevaries with the applied charge and the response can be measured on anumber of different electrodes distant from the electrode where thestimulus is applied. The responses measured in the sheep spinal cord areshown in FIG. 16, for responses in the ascending direction (i.e. forelectrodes positioned away from the stimulating electrode along themidline of the spinal cord). FIG. 22a displays the variation in evokedSCP amplitude with varying stimulus current, on four separate electrodesin the ascending direction, while FIG. 22b showing the equivalent in thedescending direction. In particular, FIG. 22 shows ascending anddescending evoked CAP N1-P2 amplitudes, recorded in sheep in response tobiphasic 40 μs stimulus pulse widths.

The amplitude of the responses for electrodes which are more distantfrom the stimulus site do not increase as markedly with the stimuluscurrent as the electrodes closer to the stimulus site. The distantelectrodes are measuring the propagation of the action potentialascending (or descending the spinal cord) and aren't subject to anylocalized recruitment phenomena. At a given stimulus level above acritical value A_(sat) the number of fibres close to the sense electrodewhich can be recorded are all recruited and increasing stimulation nolonger causes an increase in the amplitude of the response.

The different sensitivities of the different regions of measurement canbe used to estimate the target value for feedback loop control. Considerthe responses at two different positions of the electrode relative tothe stimulated tissue, in this case the spinal cord. The amplituderesponse curve in position 1 labelled p1 in FIG. 23 for electrode 1 andelectrode 5 (sub e1 and e5) are illustrated. For an alternative positionp2 the responses are scaled by the effect of the change in distance fromthe electrode. Less tissue is recruited and less evoked response ismeasured. The amplitude response of the distant electrodes is onlyweakly dependent above a saturation level S_(sat) of stimulation onchanges to the stimulus amplitude. That is, S_(sat) is an amplitudewhich is asymptotically approached by the response as seen by electrodesdistant from the stimulus.

If a completely flat response above S_(sat) is assumed, then the scalingfactor due to the shift in distance for this electrode is simply theratios of the responses at the large electrode separations (Equation 1).

R _(e1p2)=(S _(s) +A _(s))R _(e1p1)  Equation 1

The response measured is scaled by a factor S_(S) which relates to thechanged measurement sensitivity, and by a factor A_(S) which relates tothe change in the amplitude due to the change in the recruitment level.For the case when the amplitude at a distant electrode is weaklydependent on the stimulation current, then:

R _(e5p2)=(S _(s) +A _(s))R _(e5p1)  Equation 2

and so

(R _(e1p2) /R _(e1p1))−(R _(e5p2) /R _(e5p1))=A _(s)  Equation 3

Knowing A_(s) thus permits estimation of actual neural recruitment fromthe measured response, even in the presence of varyingelectrode-to-fibre distance d.

A second embodiment for estimating neural recruitment in the presence ofvarying electrode-to-fibre distance d, is based on a two point method.The evoked response measured on one electrode has an almost lineardependence on the applied current, in the operating region betweenthreshold and saturation and for a given stimulation pulse width. Theresponse changes (independent of pulse width) with applied charge. If weconsider two response curves at two different postures P1 and P2, thenthey will have different amplitude and saturation point, which willdepend on the separation of the electrode from the tissue in eachrespective posture.

For a fixed electrical activity in the spinal cord the effect of movingthe sense electrode away will be to scale the response curve by thefactor which relates to the separation. The electrical activity howeverchanges because in this case the sense electrode and the stimulatingelectrode are both moving with respect to the spinal cord. Movement ofthe stimulating electrode away from the spinal cord has the effect oflowering the resultant induced electrical activity in the spinal cordbecause of a reduction in the field strength and this has the effect ofshifting the threshold.

FIG. 24 shows SCP amplitude response curves for two different postures,indicating slope determination via a 2-point method. The slope and thethresholds of the linear responses can simply be determined from themeasurement of the responses at two different current (stimulation)levels in the linear portion of the respective amplitude growth curve.More stimulation levels may be employed to generate more accurateestimates of the slope and the response. For the two different posturesP1 and P2 reflected in FIG. 24 the response is measured for twodifferent stimulus intensities S1 and S2, which generate four differentresponses.

The equation of the respective line is simply:

r=R _(s2p1)+((R _(s1p1) −R _(s2p1))/(S ₁ −S ₂))*(s−S ₂)  Equation 4

for P1, and

r=R _(s2p2)+((R _(s1p2) −R _(s2p2))/(S ₁ −S ₂))*(s−S ₂)  Equation 5

for P2.

The strength of recruitment is not related directly to the responserecorded, due to the influence of the displacement upon the senseelectrode. However, the intercept of the line of equation 4 or 5 withthe x axis approximates the threshold, i.e. the minimum stimulus atwhich a neural response arises. The threshold can then be used toestablish the stimulus parameter control loop variable to respond tochanging d.

T _(p1) =R _(s2p1)−((R _(s1p1) −R _(s2p1))/(S ₁ −S ₂))*S ₂  Equation 6

The threshold scales with the influence of the change in electric fieldas a result of the displacement. In order to achieve a constant level ofrecruitment the threshold estimate determined in this manner can be usedto determine the target response signal for the control loop.

FIG. 25 shows exemplary data collected from a human subject in threedifferent postures: lying prone, lying supine, and reclining. Thepeak-to-peak amplitude is plotted against the stimulation current. Thethreshold values calculated from linear fits to the straight line of thetype set out in equations 4 and 5 can be used to estimate the stimulusrequired to achieve the same level of neural recruitment, independent ofthe position of the electrode. As can be seen in FIG. 25, the techniqueof this embodiment of the invention provides strong differentiationbetween user postures, permitting automated feedback control of changedpostures. Moreover, FIG. 25 reveals that if the stimulus was adjusted togive the same amplitude of the measurement of evoked response, thestimulus value would be in error by 20% in the two extremes of theposture.

The stimulus intensity scaled by the threshold value corresponds to apsycho-physical percept of the paraesthesia. For the individual whosedata is displayed in FIG. 25, threshold corresponded to sensation on theleft leg. The threshold was measured by adjustment of the stimulusintensity and asking the patient to describe the location and strengthof the sensation. This task was performed in three different postures,with the patient sitting up, on their back and lying on the stomach,represented in the three rows of Table 1. The first sensationexperienced was in the left leg, and the calculated thresholds fromlinear fits to the lines as per equations 4 and 5 correspond well withthe measured thresholds. As the stimulus intensity increased, the rangeof coverage increased, covering both legs. The stimulus level requiredto achieve this psycho-physical threshold is different at all thedifferent postures. The stimulation current required to produce anidentical psycho-physical response irrespective of the posture can becalculated from the threshold value (for that current posture),multiplied by a scaling factor determined from the measurement atanother different posture.

TABLE 1 Thresholds Both Lower mA Leg Legs Measured Back Measured  3.9  5 4.0  6  6.7 10 14.2 12 14.8 16 24.5 24 19.2 16 20   33  

Thus, electrically activated compound action potential can be used topredict the stimulation level required to achieve a constantpsychophysical percept.

A further embodiment for estimating neural recruitment even in thepresence of varying electrode-to-fibre distance d, is based on peakposition within the measured neural response. The recruitment of a nervefibre in an electric field is a probabilistic event. Increasing theelectric field strength increases the probability of firing. The higherthe field strength the more likely any one nerve will fire and thefiring of those nerves will become more and more synchronised. Theresult of the synchronisation is a sharpening of the peak and shift ofthe peak closer toward the stimulus time. The recorded peak will have ashorter interval from the onset of stimulus to peak height for higherstimulation intensities. Peak position thus presents a signal featurewhich may be analysed to assess actual recruitment.

A further embodiment for estimating neural recruitment even in thepresence of varying electrode-to-fibre distance d, is based on spectralcharacteristics of the measured neural response. As the distance dchanges, the fibre-to-electrode transimpedance function shape changes,as can be understood by reference to the cable model of a myelinatedaxon, for convolutional modelling. A myelinated axon consists of a tubeformed of active axonal membrane, sheathed in a layer of insulatingmyelin. This myelin sheath is interrupted at regular intervals, exposingthe membrane to the external medium. These gaps, the nodes of Ranvier,occur at intervals of approximately 100 times the axon diameter, acrossmany types of myelinated nerve. This physical structure permits analysiswith a discrete cable model, the inside of the axon is assumed to be ahomogeneous conductor, while the membrane ion channel dynamics can bemodelled as a nonlinear, time-variant conductance across the membrane atthe nodes of Ranvier

The change in shape of the fibre-to-electrode transimpedance function inresponse to a change in d has the effect of smearing the SCP out in timewith increased distance, which also reduces its peak-to-peak amplitude.This time-domain change can be measured independently of amplitude, toobtain a direct estimate of distance variation.

The propagating action potential in a single fibre is related to acorresponding action current through the fibre's cell membrane. Afterthe AP is initiated in the fibre, the change in potential at one pointin the fibre causes ion channels in the nearby membrane to open andclose, permitting the flow of a current which then changes the potentialfurther along. In this way, the action current/potential propagatecontinuously along unmyelinated fibres (such as C fibres), and jump fromnode to node along myelinated fibres (such as A and A fibres). Actionpotentials propagating along many nerves in a bundle give rise to ameasurable compound action potential (CAP). This measured potential isthe sum of the effects of the individual action currents along eachfibre; a strong current into the fibre is seen at the leading edge ofthe activation, while an out-ward current follows, as the fibre'smembrane recovers. This may be modelled, for each point on the fibre, asexperiencing a fixed action current waveform, delayed proportional tothe point's distance from the site of initiation. These currents suminto a potential, due to the resistive nature of the tissues and fluidsinvolved, and for simple cases, may be modelled as a simple volumeconductor.

In this case, there is a function for the current at any time at anypoint along the fibre I(t,x); given the current under the activationsite I(t,0)=I₀(t) and the speed with which the activation propagates, v,this is given by:

I(t,x)=I ₀ t−x/v

For a linear medium, there is also a transfer function F(x) from thecurrent at any point along the fibre to the induced voltage on themeasuring electrode V:

V(t)=Σ×F(x)I(t,x)

With suitable scaling, it can then be seen that the measured potentialfrom a propagating action current in a single fibre is given by theconvolution of I₀ with F. Letting F′(x)=F (vx):

V(t)=Σ×F′(x)I ₀(t−x)=F′*I ₀

F in a simple volume conductor has a definition similar to

F(x)=1/(d ² +x ²)

where d is the fibre-electrode distance, and x is the position along thefibre (relative to the electrode).

Due to the convolution equivalence, we can see that F acts as atime-domain filter kernel applied to I; and since the shape, and hencespectral characteristics, change with d, the filter will exhibitdifferent spectral characteristics at different distances. Thisrecognition can be exploited by, for example, picking two frequencieswhich are prominent in the compound action potential. By examining theratio of the selected frequencies, changes in electrode-to-cord distancecan be measured, regardless of recruitment percentage.

One key benefit of adjusting programming parameters on the basis ofneural response measurements is the ability to understand the relativeposition of the therapeutic stimulus in the amplitude growth curve.There are two distinct tasks required in the adjustment of programparameters for spinal cord stimulation systems and these are:

1) Matching location of paraesthesia to pain location, and

2) Achieving sufficient coverage such that the area of paraesthesiaoverlaps the area of pain.

Both these need to be achieved without side effects.

FIG. 26 is a schematic representation of an SCP amplitude growth curve,with salient features noted. Very often a clinician will find the bestelectrodes for location (step (1) above) and then wind up the current toachieve the coverage desired (step (2)). In the absence of ERT measures,it is impossible for the clinician to know where the therapeutic settingis with respect to the fast response stimulus threshold (Tf in FIG. 26)and slow response stimulus threshold (Ts).

A situation where the therapeutic level is adjusted to position C inFIG. 26 is undesirable because the stimulus is close to the slowresponse threshold. The ideal location for the therapeutic stimuluscurrent is at position B as this gives the most sensitive response tostimulus. Adjustments to the stimulus have a greater impact on theperipheral response from the individual. The problem then becomesensuring that, for a stimulus of a level B, there is sufficient coverageby the paraesthesia to correspond to the area of pain.

An alternative way to address this is by stimulating at alternatinglocations. The choice to begin to spread the stimulus locations is basedon the position of the stimulus current in the amplitude growth curve. Arule set can be developed to make those choices in an automated mannerbased on the neural response measurements. For instance, stimulation maybe applied on alternating electrodes after the current reaches a pointB.

Collection of programming data, paraesthesia coverage and neuralresponse measurements can be used to derive a set of rules for an expertsystem to set up the ideal parameters for the system. Alternating orroving stimuli can be used to extend the coverage of paraesthesia.Alternating stimuli can be used with all stimuli output at the optimalrate (for example 40 Hz).

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention as shown inthe specific embodiments without departing from the spirit or scope ofthe invention as broadly described. For example, embodiments describedin the context of spinal cord stimulation may in some cases be appliedto other forms of neural stimulation and it is to be understood thatsuch other contexts are within the scope of the present invention. Thepresent embodiments are, therefore, to be considered in all respects asillustrative and not restrictive.

1. (canceled)
 2. A method of controlling a neural stimulus, the methodcomprising: applying a neural stimulus from an electrode arraycomprising at least one stimulus electrode to a neural pathway of apatient, the stimulus being defined by at least one stimulus parameter,the electrode array being subject to movement relative to the neuralpathway; measuring a neural response evoked by the stimulus, the neuralresponse comprising an evoked compound action potential, wherein adistance between the electrode array and the neural pathway is subjectto change induced by movement of the electrode array relative to theneural pathway; deriving from the measured neural response a feedbackvariable; comparing a target value with the feedback variable;adjusting, based on the comparison, a value of the at least one stimulusparameter; and repeating the applying, measuring, deriving, andadjusting, wherein the adjusting or the comparing reduces variations inrecruitment induced by the change in distance.
 3. The method of claim 2,wherein the adjusting comprises applying a compensating function to thefeedback variable that compensates for altered measurement sensitivityresulting from the change in distance.
 4. The method of claim 3, whereinthe compensated feedback variable is representative of neuralrecruitment.
 5. The method of claim 3, wherein applying the compensatingfunction comprises: estimating the distance between the electrode arrayand the neural pathway, and scaling the feedback variable based on theestimated distance.
 6. The method of claim 5, wherein estimating thedistance comprises: applying a probe stimulus to the neural pathway;measuring a neural response evoked by the probe stimulus; and estimatingthe distance relative to a calibration point using the measuredresponse.
 7. The method of claim 5, wherein estimating the distancecomprises using spectral characteristics of the measured neuralresponse.
 8. The method of claim 3, wherein applying the compensatingfunction comprises: estimating a distance-dependent scaling factor, andscaling the feedback variable using the distance-dependent scalingfactor.
 9. The method of claim 8, wherein estimating thedistance-dependent scaling factor comprises: measuring a neural responseevoked by the stimulus at a distant sense electrode; computing a firstratio, being a ratio of an intensity of the evoked neural response atthe distant sense electrode to an intensity of an evoked neural responsemeasured at the distant electrode at a reference distance; computing asecond ratio, being a ratio of the intensity of the measured neuralresponse to an intensity of an evoked neural response measured at thereference distance; and estimating the distance-dependent scaling factorby subtracting the first ratio from the second ratio.
 10. The method ofclaim 2, further comprising adjusting the target value so as to reducevariations in recruitment induced by induced by the change in distance.11. The method of claim 10, wherein adjusting the target valuecomprises: estimating a threshold, being a minimum stimulus at which aneural response arises, and scaling a base target by the estimatedthreshold.
 12. The method of claim 2, wherein the feedback variablecomprises a peak-to-peak amplitude of the measured neural response. 13.An implantable device for controllably applying a neural stimulus, thedevice comprising: an electrode array comprising one or more stimuluselectrodes and one or more sense electrodes; a stimulus sourceconfigured to deliver a stimulus via the one or more stimulus electrodesto a neural pathway, the electrode array being subject to movementrelative to the neural pathway; measurement circuitry for measuring aneural response sensed at the one or more sense electrodes; and acontrol unit configured to: control application of a neural stimulus asdefined by at least one stimulus parameter; measure via the measurementcircuitry a neural response evoked by the stimulus, the neural responsecomprising an evoked compound action potential, wherein a distancebetween the electrode array and the neural pathway is subject to changeinduced by movement of the electrode array relative to the neuralpathway; derive from the measured neural response a feedback variable;compare a target value with the feedback variable; and adjust, based onthe comparison, a value of the at least one stimulus parameter, whereinthe adjusting or the comparing reduces variations in recruitment inducedby the change in distance.
 14. The implantable device of claim 13,wherein the adjusting comprises applying a compensating function to thefeedback variable that compensates for altered measurement sensitivityresulting from the change in distance.
 15. The implantable device ofclaim 14, wherein the compensated feedback variable is representative ofneural recruitment.
 16. The implantable device of claim 14, whereinapplying the compensating function comprises: estimating the distancebetween the electrode array and the neural pathway, and scaling thefeedback variable based on the estimated distance.
 17. The implantabledevice of claim 16, wherein estimating the distance comprises: applyinga probe stimulus to the neural pathway; measuring a neural responseevoked by the probe stimulus; and estimating the distance relative to acalibration point using the measured response.
 18. The implantabledevice of claim 16, wherein estimating the distance comprises usingspectral characteristics of the measured neural response.
 19. Theimplantable device of claim 14, wherein applying the compensatingfunction comprises: estimating a distance-dependent scaling factor, andscaling the feedback variable using the distance-dependent scalingfactor.
 20. The implantable device of claim 19, wherein estimating thedistance-dependent scaling factor comprises: measuring a neural responseevoked by the stimulus at a distant sense electrode; computing a firstratio, being a ratio of an intensity of the evoked neural response atthe distant sense electrode to an intensity of an evoked neural responsemeasured at the distant electrode at a reference distance; computing asecond ratio, being a ratio of the intensity of the measured neuralresponse to an intensity of an evoked neural response measured at thereference distance; and estimating the distance-dependent scaling factorby subtracting the first ratio from the second ratio.
 21. Theimplantable device of claim 13, wherein the control unit is furtherconfigured to adjust the target value so as to reduce variations inrecruitment induced by induced by the change in distance.
 22. Theimplantable device of claim 21, wherein adjusting the target valuecomprises: estimating a threshold, being a minimum stimulus at which aneural response arises, and scaling a base target by the estimatedthreshold.
 23. The implantable device of claim 13, wherein the feedbackvariable comprises a peak-to-peak amplitude of the measured neuralresponse.